Solution for removing cataracts via liquefracture

ABSTRACT

An improved solution for use in the removal of cataractous lenses via liquefracture is described. The liquefracture solution contains a viscosity-enhancing agent to increase the residence time of the solution in the heating chamber of the liquefracture handpiece, thereby increasing the expulsion force of the solution from the handpiece (i.e., “pulse force”). An agent that releases gas when the liquefracture solution is heated in the handpiece may also be included in the solution, thereby also enhancing the pulse force of the solution upon expulsion from the handpiece. The solution preferably also contains a partially water-soluble agent that forms a temporarily insoluble precipitate when heated in a liquefracture handpiece. The precipitate acts as an abrasive agent when expelled with the liquefracture solution from the handpiece, thereby facilitating the cutting and disintegration of the cataractous lens material.

This application claims priority from International Patent ApplicationNo. PCT/US01/47635 filed on Dec. 11, 2001, which claims priority fromU.S. Provisional Application Ser. No. 60/257,715, filed on Dec. 20,2000.

BACKGROUND OF THE INVENTION

The present invention is directed to the field of ophthalmic surgery.More specifically, the invention is directed to the field of proceduresand associated products for removing the natural crystalline lens of thehuman eye in patients whose lenses have become afflicted with cataractsor other conditions wherein removal of the lenses is required.

Removal of human lenses has been achieved by various surgical techniquesin the past. The most prevalent technique at this time involves aprocess known as “phacoemulsification”. This process involves the use ofa handpiece with a tip that vibrates at an ultrasonic frequency. Aftermaking a small incision in the eye, the ophthalmic surgeon employs thishandpiece to emulsify the lens within the capsular bag of the eye, andthen employs the irrigation and aspiration modes of the handpiece toremove the lens particles from the capsular bag. Millions of cataractpatients have had their cataractous lenses removed by means of thephacoemulsification procedure. Although ophthalmic surgeons havemastered the use of the phacoemulsification handpiece and associatedsurgical techniques, the use of an ultrasonic needle or tip within theeye presents inherent risks and concerns. Ophthalmic surgeons and othersskilled in the art have therefore searched for improved devices andprocedures for removing the human lens.

A new lens removal procedure known as “liquefracture” is currently beingdeveloped by Alcon Research, Ltd. This procedure is described in U.S.Pat. No. 5,616,120 (Andrew, et al.), U.S. Pat. No. 5,885,243 (Capetan,et al.), U.S. Pat. No. 5,989,212 (Sussman, et al.), U.S. Pat. No.5,997,499 (Sussman, et al.) and U.S. Pat. No. 6,080,128 (Sussman, etal.), the entire contents of the foregoing patents are herebyincorporated in the present specification by reference.

Liquefracture is a new technique wherein the lens is disintegrated byapplying hot pulses of a solution to the lens via anirrigation/aspiration handpiece. The handpiece, such as those describedin the above-cited patents, includes a chamber for heating the solutionand generating pulses of heated solution that are expelled from thehandpiece. The lens is disintegrated by means of a combination of theheat absorbed from the solution and the force of the pulses of thesolution impacting the lens tissue. The solution utilized for thispurpose is referred to herein as the “liquefracture solution”.

Due to the delicacy of the intraocular tissues, both the extent to whichthe solution can be heated and the force or velocity of the pulses arenecessarily constrained. In order to prevent damage to surroundingtissues, the stream of hot, pulsed solution is surrounded by aconventional irrigating solution which dissipates both the heat andforce of the pulsed solution after it impacts the lens tissue. Thissecond solution is referred to herein as either the “irrigatingsolution” or the “outer” or “dissipating” solution.

Prior to the present invention, the solution utilized for both theliquefracture solution and the irrigating solution has been aconventional balanced salt solution such as BSS® (Balanced SaltSolution) Sterile Irrigating Solution, which is available from AlconLaboratories, Inc., Fort Worth, Tex. Although this type of solution isgenerally adequate, there is a need for improved solutions which enhancethe disintegration of the lens with the pulsed, heated solution andfacilitate removal of the lens fragments following disintegration of thelens. The present invention is directed to filling this need.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of a means for enhancingthe effectiveness of the liquefracture solution in disintegrating thelens material during the above-described liquefracture procedure. Morespecifically, it has been discovered that the effectiveness of theliquefracture solution can be enhanced by increasing the pulse force ofthe solution. The effectiveness of the liquefracture solution can befurther enhanced by including an agent which forms a temporarilyinsoluble precipitate at the temperatures utilized to form the hot,pulsed solution, thereby resulting in particles that act as abrasiveagents.

The pulse force of the liquefracture solution is increased by includinga viscosity-enhancing agent in the solution used to form the hot, pulsedsolution, thereby increasing the length of time for which the solutionis retained in the heating/expansion chamber of the liquefracturehandpiece and permitting more energy to be stored in the pulse of fluid.The pulse force can be further enhanced by including a small amount of agas-generating propellant in the solution used to form the hot, pulsedsolution, thereby increasing the velocity or force of the hot pulsedsolution.

In a preferred embodiment of the present invention, the effectiveness ofthe liquefracture procedure is further enhanced by including aviscosity-enhancing agent in the irrigating solution utilized as theouter or dissipating solution in the procedure. The enhanced viscosityof the irrigating solution increases the ability of the solution todissipate the heat absorbed from the liquefracture solution. As aresult, the temperature or proportion of the liquefracture solution canbe increased (i.e., relative to the irrigating solution), therebyfurther enhancing the ability of the liquefracture solution todisintegrate the lens material.

The increased pulse force of the solutions of the present inventionenhances the effectiveness of the liquefracture procedure, relative tothe speed at which the lens is disintegrated and the extent to whichliquefracture can be utilized to remove relatively hard lenses. Theinclusion of an abrasive agent in the solutions further enhances theeffectiveness of the liquefracture solution by increasing the ability ofthe solutions to cut and disintegrate cataractous lens material.

DETAILED DESCRIPTION OF THE INVENTION

The improved liquefracture solutions of the present invention have beendiscovered as a result of a careful balancing of several factors. Forexample, the desired goal of enhancing the ability of the liquefracturesolution to disintegrate the lens must be balanced against otherrequired physical characteristics of the solution, such as the need forthe solution to flow through the liquefracture handpiece and associatedsurgical equipment during the surgical procedure.

The ability of a liquefracture solution to disintegrate a cataractouslens is directly dependent on the force of the pulsed solution as itimpacts the lens tissue. This force is referred to herein as the “pulseforce” of the liquefracture solution. As indicated above, it has beendiscovered that the pulse force of the liquefracture solution can beincreased by enhancing the viscosity of the liquefracture solution.Enhancing the viscosity of the liquefracture solution increases theresidence time of the solution in the heating chamber of theliquefracture handpiece, thereby increasing the energy absorbed by thesolution and increasing the force by which the solution is expulsed fromthe chamber.

Various types of agents may be utilized to enhance the viscosity of theliquefracture solution, such as chondroitin sulfate, sodium hyaluronateor other proteoglycans; cellulose derivatives, such as hydroxypropylmethylcellulose (“HPMC”), carboxy methylcellulose (“CMC”), andhydroxyethyl cellulose (“HEC”); collagen and modified collagens;galactomannans, such as guar gum, locust bean gum and tara gum, as wellas polysaccharides derived from the foregoing natural gums and similarnatural or synthetic gums containing mannose and/or galactose moietiesas the main structural components (e.g., hydroxypropyl guar); xanthangum; gellan gums; alginate; chitosans; polyvinyl alcohol; carboxyvinylpolymers (e.g., carbomers such as the Carbopol™ brand polymers availablefrom B.F. Goodrich); and various other viscous or viscoelastomericsubstances, including but not limited to those described in U.S. Pat.No. 5,409,904 (Hecht, et al.), the entire contents of which are herebyincorporated by reference in the present specification.

The following patent publications may be referred to for further detailsconcerning the above-listed viscosity-enhancing agents: U.S. Pat. No.4,861,760 (gellan gums); U.S. Pat. No. 4,255,415 and WIPO PublicationNo. WO 94/10976 (polyvinyl alcohol); U.S. Pat. No. 4,271,143(carboxyvinyl polymers); WIPO Publication No. WO 99/51273 (xanthan gum);and WIPO Publication No. WO 99/06023 (galactomannans). The entirecontents of the foregoing references pertaining to the structures,chemical properties and physical properties of the respective viscosityenhancing agents described above are hereby incorporated in the presentspecification by reference.

As demonstrated in Example 8 below, it has been found that the use ofhigher molecular weight fractions of polymeric materials as theviscosity enhancing agent is desirable, because the higher molecularweight fractions generally produce greater pulse forces than lowermolecular weight fractions of the same material. The use of highermolecular weight fractions is therefore preferred.

The most preferred viscosity-enhancing agent is HPMC at a molecularweight of 86,000 to 260,000. As discussed below, HPMC is also preferredas the transient abrasive agent of the improved liquefracture solutionsdescribed herein.

The above-described viscosity-adjusting agents will be utilized in anamount sufficient to provide the liquefracture solutions of the presentinvention with an enhanced viscosity. As utilized herein, the phrase“enhanced viscosity” means a viscosity which is greater than theviscosity of aqueous humor and standard irrigating solutions, both ofwhich generally have viscosities of approximately 1 centipoise (“cps”).The liquefracture solutions of the present invention will typically haveviscosities of from greater than 1 cps to about 15 cps, preferably fromabout 2 to about 7 cps.

The liquefracture solutions of the present invention contain one or moreof the above-described viscosity enhancing agents in an ophthalmicacceptable vehicle. Various types of solutions may be utilized as avehicle for the liquefracture solution; however, the conductivity of theliquefracture solution is a factor which must be taken into accountrelative to selection of an appropriate vehicle.

Due to the very high resistance of water, which results in lowconductivity, water does not heat up sufficiently and thus does notproduce adequate pulse force for liquefracture procedures. Ionicsolutions, such as balanced salt solution, have relatively lowerresistance to electricity, and therefore have higher conductivity. Thishigher conductivity allows the ionic salt solutions to be heatedsufficiently to be utilized in liquefracture. However, the conductivityof the solution has to be balanced with instrument design criteria, suchas the need to avoid corrosion or other damage to the liquefracturehandpiece and avoid clogging of the handpiece or other fluid channels inthe ophthalmic surgical operating system.

The liquefracture solutions are preferably formulated to be isotonic.The osmolality of the solution is an indirect measure of conductivity,since both properties are dependent on the ionic concentration. Theliquefracture solutions of the present invention preferably have anosmolality of from about 200 to about 400 milliosmoles per kilogram ofwater (mOsm/kg”).

As indicated above, the pulse force of the liquefracture solution of thepresent invention may also be enhanced by the inclusion of a propellantin the solution. The propellant comprises a gas liberating substance,such as sodium bicarbonate or sodium chlorate. In a preferred embodimentof the present invention, the liquefracture solution contains sodiumbicarbonate or sodium chlorate in a concentration of from about 1.0 toabout 2.5 w/v %.

The ability of the liquefracture solutions of the present invention tocut and disintegrate cataractous lens tissue can be further improved byincluding a transient abrasive agent in the solutions. The transientabrasive agent forms a temporarily insoluble precipitate when heated inthe liquefracture handpiece, thereby creating particles that facilitatecutting and disintegration of the cataractous lens when pulses of thehot liquefracture solution are applied to the lens, but returns tosolution as the liquefracture solution cools within the eye, therebyfacilitating removal of the solution via aspiration. This transient,temperature dependent formation of a precipitate within theliquefracture solution significantly enhances the ability of thesolution to cut and disintegrate the cataractous lens, withoutdisrupting the operation of the irrigation and aspiration modes ofophthalmic surgical systems. The materials that perform these functionsare referred to herein as “transient abrasive agents”.

Various physiologically acceptable materials may be utilized as thetransient abrasive agent. In addition to being physiologicallyacceptable, generally, and non-toxic to intraocular tissues,specifically, the transient abrasive agent must be: (1) at leastpartially soluble in aqueous electrolyte solutions at room temperatureand body temperature (i.e., temperatures of about 25° C. and 37° C.,respectively), (2) substantially insoluble at a temperature greater than50° C. and (3) chemically stable at the aforementioned temperatures.Materials that meet these criteria are referred to herein as being “anophthalmically acceptable, transient abrasive agent”.

The preferred transient abrasive agents are cellulose derivatives, suchas hydroxypropyl methylcellulose (“HPMC”), carboxy methylcellulose(“CMC”) and hydroxyethyl cellulose (“HEC”). The most preferred cellulosederivative is HPMC. HPMC is preferred based on its unique ability toform a temporarily insoluble precipitate upon heating to temperaturesabove 50° C. The other cellulose derivatives mentioned above will alsoform an insoluble precipitate when heated, but only a relatively smallportion of these cellulose materials becomes insoluble.

The selection of an ideal concentration for each class or type oftransient abrasive agent requires a balancing of the above-citedfactors. However, the concentrations selected will generally be in therange of from about 0.05 to about 0.5 weight/volume percent (w/v %).

In a preferred embodiment of the present invention, hydroxypropylmethylcellulose (“HPMC”) is utilized as the transient abrasive agent,and also increases the viscosity of the liquefracture solution, therebyenhancing both the pulse force and cutting action of the liquefracturesolution.

As indicated above, it is necessary to achieve a balance betweenenhancing the pulse force of the liquefracture solution, and maintaininga solution viscosity which is acceptable for use with theirrigating/aspiration systems employed in intraocular surgicalprocedures. If HPMC is used to enhance the viscosity of theliquefracture solution and also as the transient abrasive agent, thenthere is an additional constraint, that is, the concentration of HPMCshould not be such that its particles would clog the heating chamber ofthe liquefracture handpiece. The use of HPMC concentrations of 0.2% orhigher may result in a clogging of the irrigation/aspiration system.Consequently, it is preferred to utilize HPMC concentrations of lessthan 0.2 w/v %.

It should be noted that there is wide molecular weight range for HPMC.Increasing the molecular weight of HPMC will provide a higher viscosityat the same concentration level. In order to achieve the same viscosity,a lower concentration of higher molecular weight HPMC can be used,resulting in a lower number of particles, and hence, less potential forclogging. These two aspects of HPMC must be balanced to achieve anoptimum solution. However, the use of relatively high molecular weightforms of HPMC is preferred for the reasons stated above.

In a preferred embodiment of the present invention, the overallperformance of the liquefracture procedure is further enhanced byutilizing an irrigating solution having an enhanced viscosity as theouter or dissipating solution. The use of an enhanced viscosity solutionincreases the ability of the solution to dissipate heat from the hot,pulsed liquefracture solution, thereby making it possible to increasethe temperature of the liquefracture solution and/or increase theproportion of that solution, relative to the irrigating solution. Theviscosity-enhancing agents that may be employed for this purpose are thesame as those that may be employed to enhance the viscosity of theliquefracture solution. One or more viscosity-enhancing agents ispreferably utilized in an amount sufficient to provide the irrigatingsolution with a viscosity in the range of from about 2 to about 7 cps.

The following examples are provided to further illustrate theliquefracture solutions of the present invention.

EXAMPLE 1

Component Amount (w/v %) Function HPMC (E4M) 0.05 to 0.2 VEA/TAA* SodiumBicarbonate 1.5 Propellant Hydrochloric Acid Adjust pH pH Adjust SodiumHydroxide Adjust pH pH Adjust Water for Injection 100% Vehicle *VEA/TAA= Viscosity Enhancing Agent/Transient Abrasive Agent

The above-described formulation may be prepared as follows: First, thewater for Injection is brought close to boiling or at boiling. The HPMCis then slowly added to the water under continuous stirring tothoroughly disperse it in the water. Then the mixture is slowly allowedto cool, stirring continuously. Once at room temperature, the mixtureshould start clearing up. Then the mixture is stored overnight in anappropriate container to fully hydrate the HPMC. The following day, theremaining ingredients are added to the HPMC solution, additional waterfor injection is added if needed to bring the solution to final volume,and the final solution is filtered, packaged in bottles and autoclaved.

EXAMPLE 2

Component Amount (w/v %) Function HPMC (K100M) 0.05 to 0.2 VEA/TAASodium Bicarbonate 1.5 Propellant Hydrochloric Acid Adjust pH PH AdjustSodium Hydroxide Adjust pH PH Adjust Water for Injection 100% Vehicle

The above-described formulation may be prepared utilizing the methoddescribed in Example 1, above.

EXAMPLE 3

Component Amount (w/v %) Function HPMC (E4M) 0.05 to 0.2 VEA/TAA SodiumChloride 0.9 Tonicity Agent Water for Injection 100% Vehicle

The above-described formulation may be prepared utilizing the methoddescribed in Example 1, above.

EXAMPLE 4

Component Amount (w/v %) Function HPMC (K100M) 0.05 to 0.2 VEA/TAASodium Chloride 0.9 Tonicity Agent Water for Injection 100% Vehicle

The above-described formulation may be prepared utilizing the methoddescribed in Example 1, above.

EXAMPLE 5

Component Amount (w/v %) Function HPMC (K100M) 0.01 to 0.2 VEA/TAASodium Chloride 0.64 Tonicity Agent Potassium Chloride 0.075 TonicityAgent Calcium Chloride (Dihydrate) 0.048 Buffering Agent MagnesiumChloride 0.03 Buffering Agent (Hexahydrate) Sodium Acetate (Trihydrate)0.39 Buffering Agent Sodium Citrate (Dihydrate) 0.17 Buffering AgentHydrochloric Acid Adjust pH pH Adjust Sodium Hydroxide To 7.0–7.2 pHAdjust Water for Injection Qsd to 100 Vehicle

The above-described formulation may be prepared utilizing the methoddescribed in Example 1, above.

EXAMPLE 6

Component Amount (w/v %) Function Hydroxypropyl Methylcellulose 0.01 to0.2 VEA/TAA (HPMC) Sodium Chloride 0.744 Tonicity Agent PotassiumChloride 0.0395 Excipient Dibasic Sodium Phosphate 0.0433 BufferingAgent (Anhydrous) Sodium Bicarbonate 0.219% + 20% xs ExcipientHydrochloric Acid Adjust pH pH Adjust Sodium Hydroxide To 7.0–7.2 pHAdjust Water for Injection 100% Vehicle

The above-described formulation may be prepared utilizing the methoddescribed in Example 1, above.

EXAMPLE 7

The data set forth in the following table demonstrates the increasedpulse force that is achieved by the present invention. Morespecifically, the data show that the addition of a gas-generatingpropellant (i.e., sodium bicarbonate) enhances the pulse force of aliquefracture solution upon expulsion from the liquefracture handpiece,and show that the addition of a viscosity-enhancing agent (i.e., HPMC)to the liquefracture solution further increases pulse force.

TABLE 1 Passive Flow Formulation Description Pulse Force (g) (gms/min)Distilled Water 0 3.44 BSS ® 5–5.5 3.44 BSS PLUS ® (Part I) 5.5 3.36  1% NaHCO₃ 6.0 3.13   1% NaHCO₃ + 0.1% HPMC 6.75 3.96 (E4M grade) 1.5%NaHCO₃ + 0.1% HPMC 7.1 4.1 (E4M grade)   1% NaHCO₃ + 0.2% HPMC 8.0 4.0(E4M Grade) 1.5% NaHCO₃ + 0.05% HPMC 8.2 4.4 (K100M grade) BSS PLUS PartI + 0.1% HPMC 8.5 3.96

The pulse force evaluations were carried out using an appropriate loadcell with an analog-filtered signal, using the following parameters:10,000 scans/second; 2,000 Hz sampling frequency with 25 Hz high passcutoff frequency; 2500 Hz low pass cutoff frequency and 2,000 pointscollected. The full-scale pulse force is measured from the baseline tothe maximum height of the filtered signal, which is a relativemeasurement and not an absolute one.

The electrode or engine was a standard one of the type described U.S.Pat. Nos. 5,989,212; 5,997,499; and 6,080,128 (Sussman et al.), thecontents of which have been incorporated herein by reference. Thegraphite electrodes were set at a pulse duration of 1.7 milliseconds.During the measurement, passive pressure was adjusted such that thepassive flow rate was in the range of 3 to 4 grams per minute(“gms/min”) for optimal performance of the instrument.

EXAMPLE 8

The effect of the molecular weight of the viscosity enhancing agents onthe pulse force of the liquefracture solutions was evaluated bymeasuring and comparing the pulse forces of solutions containing threedifferent cellulose derivatives, CMC, HPMC and HEC. Solutions containingtwo different molecular weights of each cellulose derivative wereprepared using standard formulation procedures. The concentration of thecellulose polymers was adjusted in order to eliminate differences inviscosity between the test solutions. A standard ophthalmic irrigatingsolution, BSS™ (Balanced Salt Solution) Sterile Irrigation Solution, wasutilized as the control against which the enhanced viscosity solutionswere measured. The pulse force of the solutions was determined by meansof the procedures described in Example 7. The pulse force values for thetest solutions were compared to the pulse force value for the controlsolution. All of the test solutions demonstrated an increase in pulseforce, relative to the control solution. The results, expressed aspercent increase in pulse force, are presented in Table 2 below:

TABLE 2 Effect of Molecular Weight on Pulse Force Viscosity Increase inPulse Solution (cps) Mol. Wt. Force (%) BSS ® Solution 1.0 — —  0.63%NaCMC (7LFPH) 3.0 ± 0.1   90,000 35  0.18% NaCMC (7HFPH) 3.0 ± 0.1  700,000 67  0.2% HPMC (E4M) 2.9 ± 0.1   86,000 45  0.09% HPMC (K100M)3.0 ± 0.1   260,000 105 0.125% HEC (250M) 3.0 ± 0.1   720,000 75 0.075%HEC (250 HX) 3.0 ± 0.1 1,300,000 82

The results set forth in Table 2 demonstrate that for a given cellulosederivative, the use of a higher molecular weight fraction of thatderivative results in a greater pulse force. This relationship betweenmolecular weight and pulse force may be attributable to the fact thatthe higher molecular weight polymer material makes the liquefracturesolution more cohesive, thereby resulting in a more concentrated forcewhen the heated solution is expelled from the liquefracture handpiece.

The results in Table 2 show that the solution containing HPMC at amolecular weight of 260,000 exhibited a higher pulse force than thesolutions containing CMC and HEC at higher molecular weights (i.e.,molecular weights of about 700,000). This is believed to be attributableto the fact that the HPMC is acting as both a viscosity enhancing agentand as a transient abrasive agent, and the fact that HPMC is much moreeffective than CMC or HEC as a transient abrasive agent, as discussedabove.

1. An improved solution for removing cataracts by means ofliquefracture, comprising: a viscosity enhancing agent in an amountsufficient to increase the residence time of the liquefracture solutionin a heating chamber of a liquefracture handpiece, when said solution isheated in said chamber; an ophthalmically acceptable, conductive vehiclefor said viscosity-enhancing agent; an effective amount of anophthalmically acceptable, transient abrasive agent; and an amount of agas-generating agent sufficient to enhance the pulse force of thesolution upon expulsion of the solution from a liquefracture handpiece.2. An improved liquefracture solution according to claim 1, wherein theophthalmically acceptable vehicle comprises a balanced salt solution. 3.An improved liquefracture solution according to claim 2, wherein thesolution has an osmolality of 200 to 400 mOsm/kg.
 4. An improvedliquefracture solution according to claim 2, wherein the solution has aviscosity of from greater than 1 cps to 15 cps.
 5. An improvedliquefracture solution according to claim 4, wherein the solution has aviscosity of from 2 to 7 cps.
 6. An improved liquefracture solutionaccording to claim 1, wherein the viscosity enhancing agent is selectedfrom the group consisting of proteoglycans, cellulose derivatives,collagen and modified collagens, galactomannans, xanthan gum, gellangums, alginate, chitosans, polyvinyl alcohol, carboxy vinyl polymers andcombinations thereof.
 7. An improved liquefracture solution according toclaim 6, wherein the viscosity enhancing agent is a cellulosederivative.
 8. An improved liquefracture solution according to claim 7,wherein the cellulose derivative is selected from the group consistingof HPMC, CMC, HEC and combinations thereof.
 9. An improved liquefracturesolution according to claim 8, wherein the cellulose derivativecomprises HPMC.
 10. An improved liquefracture solution according toclaim 9, wherein the HPMC has a molecular weight in the range of 86,000to 260,000.
 11. An improved liquefracture solution according to claim 1,wherein the transient abrasive agent is a cellulose derivative.
 12. Animproved liquefracture solution according to claim 11, wherein thecellulose derivative comprises HPMC.
 13. An improved liquefracturesolution according to claim 12, wherein the HPMC has a molecular weightin the range of 86,000 to 260,000.